Regorafenib + Immunotherapy for Colorectal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Regorafenib, Anti-PD-1, CTLA-4

Disqualifiers: MSI-H colorectal cancer, Autoimmune disease, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—regorafenib, ipilimumab, and nivolumab—to determine the optimal dose and assess side effects in individuals with chemotherapy-resistant metastatic colorectal cancer. Regorafenib, a targeted therapy, may block enzymes that promote cancer cell growth, while ipilimumab and nivolumab enhance the immune system's ability to attack cancer. Individuals with metastatic colorectal cancer unresponsive to standard chemotherapy might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires that you have not had systemic anti-cancer treatment within 14 days or less than 5 half-lives of the first dose of the study treatment. If you are on corticosteroids or other immunosuppressive medications, you must stop them 14 days before starting the study treatment, unless they are inhaled, topical, or low-dose adrenal replacement steroids.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have tested the combination of regorafenib, ipilimumab, and nivolumab in patients with colorectal cancer. Regorafenib, approved for other cancers, stops cancer cells from growing. Ipilimumab and nivolumab help the immune system fight cancer.

Research has shown that these drugs can cause side effects. Patients have reported fatigue, skin rashes, and diarrhea as the most common issues. More serious problems, such as liver damage or severe immune reactions, are less common but possible.

This trial is in the early stages, focusing on finding the best dose and checking for side effects. While there are risks, the treatment may help slow down or shrink tumors. It is important to consult a healthcare provider to understand how this might relate to individual situations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of regorafenib, nivolumab, and ipilimumab for colorectal cancer because it brings a novel approach to treatment. Unlike traditional chemotherapy, which directly attacks cancer cells, this combination leverages the body’s immune system to fight cancer. Nivolumab and ipilimumab are immunotherapies that help the immune system recognize and destroy cancer cells more effectively. Regorafenib, a targeted therapy, works by blocking the growth of blood vessels that supply the tumor. This multi-pronged strategy could offer a more effective alternative to standard treatments, potentially improving outcomes for patients.

What evidence suggests that this treatment might be an effective treatment for colorectal cancer?

This trial will evaluate the combination of regorafenib, ipilimumab, and nivolumab for managing colorectal cancer that has spread and is resistant to other treatments. Studies have shown that this combination can slow tumor growth or even reduce tumor size in some patients. Specifically, research indicates that about 27.6% of patients experienced tumor shrinkage or halted growth. Additionally, patients had a median progression-free survival of around four months, suggesting the treatment might help delay cancer progression. This combination treatment uses immunotherapy, enhancing the immune system's ability to target and fight cancer cells. ^{1 2 3 6 7}

Who Is on the Research Team?

Marwan G Fakih

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal cancer that's stable at the microsatellite level and hasn't responded to chemotherapy. Participants should have a good performance status, acceptable organ function tests, measurable disease, and no prior treatment with the study drugs. They must not be pregnant or breastfeeding and agree to use contraception.

Inclusion Criteria

Anticipated life expectancy greater than 3 months

My liver enzymes are within the allowed range for my cancer condition.

My colorectal cancer is not microsatellite unstable.

Exclusion Criteria

I had cancer before, but it's not skin cancer or certain in situ cancers, and I'm not currently undergoing treatment.

Pregnancy or breast feeding

I have brain metastases but am stable, not on high steroids, or my steroid dose is stable or decreasing.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive regorafenib orally once daily on days 1-21, nivolumab intravenously every 2 weeks, and ipilimumab intravenously every 6 weeks. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 and 90 days, then every 3 months for up to 5 years.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Regorafenib

Trial Overview The trial is testing the combination of Regorafenib (a growth inhibitor), Ipilimumab, and Nivolumab (both immune system boosters) in patients whose colorectal cancer has spread and resisted chemotherapy. It aims to find the safest dose while observing how well these drugs work together against cancer.

How Is the Trial Designed?

Group I: Treatment (regorafenib, nivolumab, ipilimumab) Experimental Treatment 3 Interventions

Patients receive regorafenib PO QD on days 1-21, nivolumab IV over 30 minutes Q2W, and ipilimumab IV over 30 minutes Q6W. Cycles repeat every 28 day for up to 2 years in the absence of disease progression or unacceptable toxicity.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Regorafenib significantly improves median overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer (mCRC), as shown in the CORRECT trial with a regimen of 160 mg daily for 3 weeks of each 4-week cycle.

The drug has a generally acceptable tolerability profile and does not compromise health-related quality of life, making it a valuable addition to treatment options for patients with progressive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Carter, NJ.[2021]

In a study of 72 patients with microsatellite stable metastatic colorectal cancer, regorafenib or fruquintinib combined with sintilimab showed a median progression-free survival of 4.2 months and an overall survival of 10.5 months, indicating these combinations are viable third-line treatment options.

The treatment was generally well-tolerated, with only 15.3% of patients experiencing severe adverse events, and patients without liver metastasis showed better response rates and overall survival, suggesting they may benefit more from this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. Nie, C., Lv, H., Chen, B., et al.[2022]

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04362839

NCT04362839 | Regorafenib, Ipilimumab and Nivolumab ... Giving regorafenib, ipilimumab and nivolumab may slow the tumor growth and/or shrink the tumor size in patients with colorectal cancer. Detailed Description.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39504677/

Updated survival outcome of regorafenib, ipilimumab, and ... Updated survival outcome of regorafenib, ipilimumab, and nivolumab in refractory microsatellite stable non-liver metastatic colorectal cancer: A phase I ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04362839?term=AREA%5BBasicSearch%5D(AREA%5BConditionSearch%5D(%22Rectum%20Cancer%22)%20AND%20AREA%5BInterventionSearch%5D(%22nivolumab%22))&rank=10

Regorafenib, Ipilimumab and Nivolumab for the Treatment ... This phase I trial studies the side effects and best dose of regorafenib when given together with ipilimumab and nivolumab in treating patients with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9999273/

Regorafenib, Ipilimumab, and Nivolumab for Patients With ... The recommended phase 2 dose of RIN had a manageable safety profile and an overall response rate of 27.6%, a median progression-free survival of 4 months, and ...

5. jhep-reports.eu jhep-reports.eu/article/S2589-5559(25)00187-9/fulltext

Randomized phase II study comparing two doses of ... Regorafenib was initially developed to treat advanced gastrointestinal stromal tumors and colorectal cancer, and it showed efficacy in phase III trials.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11681808/

Progress of Immune Checkpoint Inhibitors Therapy for pMMR ... The REGONIVO study, reported in Japan in 2020, is a Phase I b trial that enrolled 24 patients with pMMR/MSS colorectal cancer after failure of ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0305737220300311

Evolving role of regorafenib for the treatment of advanced ... Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal ...